Immune-targeted therapy with transarterial chemo(embolization) for unresectable HCC: a systematic review and meta-analysis

Background Transarterial chemo(embolization) is preferred for treating unresectable hepatocellular carcinoma (uHCC); however, because of emerging immune-targeted therapies, its efficacy is at stake. This systematic review pioneers to evaluate the clinical efficacy and safety of transarterial chemo(embolization) combined with immune-targeted therapy for uHCC patients. Methods PubMed, Embase, and Cochrane Library were searched for studies comparing immune-targeted therapy with or without transarterial chemo(embolization) until 31 May 2024. The complete response (CR) rate, objective response rate (ORR), and disease control rate (DCR) were considered to be the primary outcomes calculated for the clinical outcomes of transarterial chemo(embolization) combined with immune-targeted therapy, along with progression-free survival (PFS) and overall survival (OS). The incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. Results Sixteen studies, encompassing 1,789 patients receiving transarterial chemo(embolization) plus immune-targeted therapy and 1,215 patients receiving immune-targeted therapy alone, were considered eligible. The combination of transarterial chemo(embolization) and immune-targeted therapy demonstrated enhanced outcomes in CR (OR = 2.12, 95% CI = 1.35–3.31), ORR (OR = 2.78, 95% CI = 2.15–3.61), DCR (OR = 2.46, 95% CI = 1.72–3.52), PFS (HR = 0.59, 95% CI = 0.50–0.70), and OS (HR = 0.51, 95% CI = 0.44–0.59), albeit accompanied by a surge in ALT (OR = 2.17, 95% CI = 1.28–3.68) and AST (OR = 2.28, 95% CI = 1.42–3.65). The advantages of additional transarterial chemo(embolization) to immune-targeted therapy were also verified in subgroups of first-line treatment, intervention techniques, with or without extrahepatic metastasis, Child–Pugh grade A or B, and with or without tumor thrombus. Conclusion The combination of transarterial chemo(embolization) and immune-targeted therapy seems to bolster local control and long-term efficacy in uHCC, albeit at the expense of hepatic complications. Systematic review registration http://www.crd.york.ac.uk/PROSPERO/, identifier 474669.


Introduction
In 2020, primary liver cancer was recognized as the sixth most prevalent malignant tumor globally, among which hepatocellular carcinoma (HCC) accounts for more than 90% of the cases (1).The majority of HCC cases have lost the chance of radical hepatectomy mainly because HCC generally progresses asymptomatically (2).It is diagnosed at an intermediate to advanced stage, also termed unresectable HCC (uHCC).The inception of the IMbrave150 trial heralded a new epoch in the utilization of targeted agents and immunotherapy for uHCC management, boasting an objective response rate (ORR) of 28% (3).This regimen, along with ap atinib a nd c amrelizu ma b (4 ) and lenvatinib and pembrolizumab (5), signifies a promising stride, albeit with an unsatisfactory median overall survival (OS).
Transcatheter arterial chemoembolization (TACE), as one of the classical transarterial therapies, is considered the standard treatment for uHCC (6).Conversely, hepatic artery infusion chemotherapy (HAIC), an emerging transarterial therapeutic modality, demonstrates noninferior local control compared to TACE but superior long-term outcomes (7,8).Despite these advancements, the advent of targeted agents and immunotherapy warrants re-evaluating the role of transarterial chemo(embolization) in HCC management.The IMbrave150 trial demonstrated the potential of integrating transarterial chemo(embolization) with targeted agents and immunotherapy (3,9), hinting at a synergistic interaction.In theory, transarterial chemo(embolization) could enhance tumor antigen release and immunogenicity; bolster the infiltration of CD4 + T, CD8 + T, and NK cells; and elicit proinflammatory responses (10,11), thereby fostering a conducive microenvironment for immune checkpoint inhibitors (ICIs).Concurrently, it can increase the expression of vascular endothelial growth factor (12,13), hinting at a viable partnership with angiogenic blockers.
Preliminary studies have witnessed the promise of immunetargeted therapy with transarterial chemo(embolization) for uHCC in the recent three years (14)(15)(16), which was reiterated by a systematic review (17).However, most of the studies were retrospective, single-center, non-comparative analyses.In the recent two years, researchers have reported encouraging results upon comparing immune-targeted therapy with transarterial chemo(embolization) for uHCC (18)(19)(20); nonetheless, adding transarterial therapy to the targeted agents and immunotherapy appears debatable (21).Consequently, we embarked on this metaanalysis to juxtapose the efficacy and toxicity profiles of immunetargeted therapy with or without transarterial therapies for uHCC.

Literature search
This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, which was also registered at http:// www.crd.york.ac.uk/PROSPERO/ (Review registry 474669).An ethics statement was not required because this study was based exclusively on published research.A comprehensive search was executed in PubMed, Medline, Embase, the Cochrane Library, and Web of Science to identify publications concerning immunetargeted therapy with or without transarterial chemo (embolization) for uHCC.Supplementary Table S1 summarizes the search strategy.A supplementary search in gray literature was conducted by reviewing conference proceedings and reference lists of key articles.The publications were not confined to any specific language, provided that they had an abstract in English to ensure data reproducibility.The literature search was independently conducted by two researchers from 1 February 2023 to 31 May 2024, based on predefined search strategies.

Literature screening and data acquisition
First, data collected through electronic or manual searches were imported to EndNote version X9 software (Clarivate) to detect duplicate records.Then, two reviewers (Huipeng Fang and Qiao Ke) conducted literature screening based on the inclusion and exclusion criteria (Supplementary Table S2).In case of any discrepancy between reviewers, a third-party reviewer was consulted to reach a final decision.
Information of the eligible studies was extracted directly by two independent researchers (Huipeng Fang and Qiao Ke) using a predefined format, encompassing data on publication, study design, baseline characteristics in each study, and endpoints.Data were cross-validated between researchers, and discrepancies were resolved through a multidisciplinary team (MDT) discussion, including at least one senior doctor.
Endpoints in this meta-analysis included the complete response (CR) rate, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).Tumor response was evaluated based on the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) or Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (22).ORR was calculated as the proportion of patients with the best response of CR or partial response (PR).DCR was calculated as the proportion of patients with the best response of ORR or stable disease (SD).PFS was defined as the duration from the initiation of treatment to the onset of disease progression or mortality from any cause.OS was defined as the time from treatment initiation to cancer-related death.AEs were evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 or 5.0, with a grade ≥3 indicating severe AEs.

Quality assessment
Considering the retrospective nature of the included studies, the quality was evaluated using a modified Newcastle-Ottawa Scale (NOS) (23).The risk of bias was graphically represented for the following elements: i) clarity in the objective definition; ii) provision of a clear triple combination of TACE/HAIC, TKIs, and ICIs; iii) provision of response assessment criteria (i.e., RECIST or mRECIST); and iv) clear definition of outcomes including CR, ORR, DCR, and AEs.

Statistical analysis
Comparison analysis between two groups was conducted using RevMan Version 5.3.The odds ratio (OR) was calculated to compare the effect size of CR, ORR, DCR, and AEs with 95% confidence interval (CI), as well as the hazard ratio (HR) for OS and PFS.The c² test and I 2 statistics were used to evaluate the heterogeneity among the included studies.P >0.10 and I 2 <50% suggested no apparent heterogeneity, and the fixed-effects model was used to estimate the effect size; otherwise, the random-effects model was used (24).Sensitivity analysis was carried out by removing each of the included studies sequentially to determine the reliability of the results.Additionally, subgroup analyses were also conducted to decrease the heterogeneity among the included studies.Publication bias was determined using the funnel plot with Egger's and Begg's tests (25,26).In this study, a P-value <0.05 indicated statistical significance.

Search results
Initially, 2,683 records were identified through electronic database search, apart from 11 records via manual searching.We excluded 108 duplicate studies, 2,586 studies upon screening titles and abstracts, and 92 studies after full-text review.Finally, 16 studies were considered eligible for this meta-analysis (Figure 1).Potential time and center crossover were noted among the studies, particularly between the studies of Mei et al. (27) and Fu et al. (28) from similar single-center and multicenter studies because of numerous participations by some centers.
All of the included studies originated from China; six were multicentered (16,(29)(30)(31)(32)(33) and five underwent PSM analysis (34-38) and one underwent sIPTW analysis (33).A total of 3,004 patients were included in this meta-analysis, encompassing 1,789 patients administered with transarterial chemo(embolization) plus immune-targeted therapy and 1,215 patients receiving immunetargeted therapy alone, respectively.Table 1 summarizes the baseline characteristics and quality assessment outcomes.Supplementary Table S3 summarizes the treatment regimens, considering no consensus on the transarterial chemo (embolization) plus immune-targeted therapy.Supplementary Figure S1 illustrates the quality of each study.Supplementary Table S4 summarizes the scoring rules of each study.
Liver function is the bottleneck of additional transarterial chemo(embolization) to immune-targeted therapy (43).In this meta-analysis, seven studies (27,28,(32)(33)(34)(35)37) compared patients with a Child-Pugh grade of A and B. Compared with the control group, the pooled HRs for both PFS and OS were in favor of the experiment group among patients with a Child-Pugh grade of A or B (all P < 0.05, Supplementary Table S6).

A B
Forest plot of progression-free survival (A) and overall survival (B) of immune-targeted therapy with or without transarterial chemo(embolization).

Discussion
Traditionally, transarterial chemo(embolization) has been the preferred option for uHCC (6,46,47); however, its role is debatable in the era of immune-targeted therapy.To the best of our knowledge, this is the first meta-analysis to compare the clinical efficacy and safety of transarterial chemo(embolization) plus immune-targeted therapy versus immune-targeted therapy.This meta-analysis consisted of 16 studies, encompassing 1,789 patients who received transarterial chemo(embolization) plus immunetargeted therapy and 1,215 patients who received immunetargeted therapy.The results elucidated that transarterial chemo (embolization) plus immune-targeted therapy outperformed <0.001 immune-targeted therapy alone in terms of CR, ORR, DCR, PFS, and OS, albeit at the cost of escalated AEs concerning liver function.
A meta-analysis confirmed the superiority of transarterial chemo(embolization) combined with immune-targeted therapy over transarterial chemo(embolization) combined with TKIs regarding the short-and long-term outcomes (57).Unlike TACE combined with TKIs, immune-targeted therapy is preferred for uHCC management globally (6,58).Our analysis demonstrated that a combination of TACE and immune-targeted therapy significantly bolstered the CR, ORR, and DCR and extended PFS and OS, compared with immune-targeted therapy alone.Noteworthy, the advantage of additional transarterial chemo (embolization) was also corroborated across various clinical scenarios (first-line treatment, TACE or HAIC, with or without extrahepatic metastasis, Child-Pugh A or B, and with or without tumor thrombus, Supplementary Table S6).These findings suggested that additional transarterial chemo(embolization) could potentially ameliorate the prognosis of uHCC, albeit necessitating higher-tier evidence from future studies.
CR and subsequent conversion hepatectomy have gained attention for uHCC (30,59).Previous non-comparative studies have demonstrated a CR rate and conversion rate of 48% and 60%, respectively (60).However, in this meta-analysis, the CR rate was only reported in 14 studies and the conversion rate was reported in three studies (28,29,39), respectively.Moreover, the CR rate ranged from 0% to 22%, which was far beyond people's expectations.This paucity of data warrants a deeper exploration, particularly concerning whether a larger sample size may diminish the perceived benefits of additional transarterial chemo(embolization).
Researchers have underscored the potential of TACE to exacerbate liver damage (61,62); hence, it is primarily recommended for patients with robust liver function (50,63).Studies have demonstrated the tolerability of adjunctive TACE to immune-targeted therapy across both single-center (14,31,64) and multicenter settings (16,30), consistent with systematic reviews (17,57).However, a significant uptick in AEs was revealed in six studies (27,28,33,37,40,41), predominantly centering on impaired liver function.Furthermore, we found that the pooled rates of elevated ALT and AST were significantly higher in the transarterial chemo (embolization) plus targeted immunotherapy group than in immune-targeted therapy alone (31.3% vs. 21.6%,32.2% vs. 24.3%,P < 0.05, Table 2).The larger sample size in this analysis unveils these AEs, which are scarcely highlighted in single studies, underscoring the need for safety assessments in larger cohorts.However, other liver function-related indexes such as total bilirubin and prothrombin time and the occurring timepoint of AEs were rarely reported, which deserve more attention in ongoing RCTs.Considering that the safety profile of immune-targeted therapy has been fully inspected in both large RCTs and real-world studies, additional transarterial chemo(embolization) might be the choke point of safety.
Nonetheless, there were several limitations in this metaanalysis.First, the retrospective design of the included studies may have resulted in confounding bias, despite five studies (29,34,35,37,38) utilizing PSM.Second, reporting bias, notably regarding CR rate and conversion rate, was also inevitable.Third, the inherent heterogeneity within the uHCC patient population would potentially circumscribe the generalizability of our findings beyond this demographic, aside from the differences in the regimen of transarterial chemo(embolization) and immune-targeted therapy.Fourth, immune-targeted therapy is initiated immediately after transarterial chemo(embolization); therefore, the timing of AEs concerning liver function needs to be described.AST and ALT were possibly elevated after transarterial chemo(embolization), suggesting its therapeutic effect.Finally, all studies were from China, and the findings would be applicable only in China.

Conclusion
With the available data, the combination of transarterial chemo (embolization) and immune-targeted therapy surpasses immunetargeted therapy alone regarding local control and long-term efficacy.However, the adjunctive use of transarterial chemo (embolization) escalates the incidence of liver function-related AEs.

TABLE 1
Basic characteristics and quality assessment of the included studies.

TABLE 2
Treatment-related adverse events.